5, 5-dioxodibenzo[1, 2, 5]thiadiazepines and process



3,322,789 Patented May 30, I967 3,322,789 5,S-DIOXODIBENZO[1,2,5]THIADIAZEPINES AND PROCESS William E. Kreighbaum, Evansville, Ind., assignor to Mead Johnson & Company, Evansville, Ind, 21 corporation of Indiana No Drawing. Filed Dec. 6, 1963, Ser. No. 328,506 10 Claims. (Cl. 260-327) The present invention is concerned with pharmaceutical products having the following structural formula, the acid addition salts thereof and chemical intermediates for production of these products.

I 7 SOZ'N 6 R2 I Alk-N \I-I Formula I These substances belong to the class of organic compounds known as the 5,5-dioxodibenzo[l,2,5]thiadiazepines for which there is no precedent in the chemical literature. The various positions of the ring are numbered in Formula I according to the system used for nomenclature purposes.

In the above formula R is a hydrogen atom or from one to two substitutent selected from halogen, methyl, trifluoromethyl, alkoxy, alkythio, and alkylsulfonyl. These substituents contain a maximum of four carbon atoms.

R is an alkyl group having one to four carbon atoms or benzyl.

R is a hydrogen atom or a halogen, methyl, trifluoromethyl, dimethylamino, dimethylsulfamyl, carbalkoxy, alkylthio, alkylsulfonyl, alkoxy, or alkanoyl group. It, too, contains a maximum of four carbon atoms.

Alk is a divalent alkylene chain containing a maximum of five carbon atoms and is selected from ethylene and trimethylene which may have one alkyl substituent containing one or two carbon atoms. Alk is joined at one end to the nitrogen atom in the ll-position of the dibenzothiadiazepine nucleus, and at the other to the NR H group.

The symbol NR H represents an amino group Wherein R contains up to four carbon atoms and is either alkyl, or hydroxyalkyl.

Preferred compounds of the present invention are comprised of those in which R and R are hydrogen, R is methyl, Alk is ethylene, methylethylene, trimethylene, or methyltrimethylene, and R is lower alkyl containing up to four carbon atoms.

The pharmaceutical products of this invention illustrated by Formula I are useful as psychotropic agents. They have low toxicities and a remarkable freedom from side effects. They may be administered orally or parenterally in doses in the range 0.1 to 100 ing/kg.

For therapeutic purposes, the free base form or the nontoxic salts are selected. Those acid addition salts having pharmaceutical elegance such as appropriate solubility characteristics, lack of hygroscopicity, stability, lack of taste or irritating propensity, etc., are preferred. Salts of this category are referred to as pharmaceutically acceptable and include the hydrochloride, hydrobromide, hydroiodide, hydrofluoride, sulfate, phosphate, methanesulfonate, acetate, propionate, benzoate, tartrate, citrate, mucate, maleate, and gluconate salts. Other salts which are not pharmaceutically preferred are also included within the present invention, however, since they are frequently useful as intermediates for purification purposes,

and in the case of optically active products for resolution purposes. Other such salts include the p-tolucnesulfonate, d-camphorsulfonate, lauryl sulfate, and others.

The products of Formula I are prepared by hydrolysis of intermediates having the structure shown in Formula II. The compounds of Formula II are also considered part of the present invention.

.ill Y Formula II The symbols R R R and Alk have the same meaning as given for Formula I. Y refers to a substituent which on hydrolysis yields the group -NR H described in Formula I.

More specifically, Y is the group NR'CO R. R is an alkyl group having up to four carbon atoms such as methyl, ethyl, isopropyl, and butyl. R is selected from alkyl and hydroxyalkyl having up to four carbon atoms, acyloxy alkyl having up to four carbon atoms in the alkyl portion and four carbon atoms in the acyloxy portion thereof.

The intermediates of Formula II are also considered part of the present invention. They are transformed into the pharmaceutical products of Formula I by hydrolysis under either acidic or alkaline conditions, but preferably the latter. Conditions known to those skilled in the art to be suitable for the hydrolysis of carboxamides are applicable for this transformation. Of course, when R or R is a substituent which is sensitive to the hydrolysis condition selected, other conditions which do not result in transformation thereof may sometimes be selected. In

P some instances, however, this is difficult to do and further operation on the R or R substituent as a concluding step to restore it to the desired form may be necessary. An example of this is when R is carbalkoxy. It i hydrolyzed to carboxyl in the course of hydrolyzing Y. It can either be retained as such in the final product or again esterified in conventional fashion to restore it to the carbalkoxy form. Conventional methods of esterification such as reaction with an alcohol under acidic conditions are applicable.

Convenient conditions for the transformation of the intermediates of Formula II to the products of Formula I include refluxing in an alkanol with sodium hydroxide or potassium hydroxide. Butanol has been found to be a convenient reaction medium employing potassium hydroxide, approximately 1 equivalent, and a reflux period of from about 2 to 24 hrs.

The intermediates of Formula II are prepared by one of two general procedures. The first involves the dealkylation of an N-methyl tertiary amino homolog of a product of Formula I in which R is an alkyl substituent having up to four carbon atom and including methyl, ethyl, propyl, and butyl. This transformation is illustrated by the equation shown below in which partial structures illustrating only the 11-position substituent are employed. The

R -Alk-N CH3 starting materials (Formula III) are described in copending application Ser. No. 328,460 of Abraham Weber filed herewith, now US. Patent 3,274,058, where they are referred to as psychotropic agents.

1|\ Alkyl N Alkyl N Alkyl Alk-N Alk-N lk-N 0 H3 002R H Formula III The demethylation method is conveniently accomplished by treatment of a compound of Formula 111 with a lower alkyl chloroformate at a temperature in the range of about 80-150 C. employing a reaction inert solvent as vehicle. Suitable solvents include benzene, toluene, xylene, dibutyl ether, tetrahydrofuran, tetrahydropyran, etc. Nonhydroxylic solvents are preferred and, of course, those solvents such as esters which are sensitive to hydrolysis under the reaction conditions are not generally suitable.

The second general procedure may be referred to as an alkylation process. It involves reaction of an aminoalkyl halide of Formula IV with a 6-alkyl or 6-benzyl-5,5- dioxodibenzo[1,2,5]thiadiazepine of Formula V shown below. The latter may also contain R R and R substituents having the same meaning as above. X is a halogen atom selected from chlorine, bromine, and iodine. Preparation of the raw materials of Formula V is described in copending application Ser. No. 328,476 of Abraham Weber filed herewith, now US. Patent 3,268,- 557.

Re I S 03'N\ /R! R R X-Alk-N Formula II com Formula V Formula IV The condensation illustrated by this equation is preferably carried out under anhydrous conditions employing an inert organic liquid as reaction medium. A strong base is required as condensing agent in carrying out this process and elevated temperatures of the order of 80-200 C. assist in bringing reaction to completion within a convenient period of time.

The strong alkali metal bases such as the oxides, alkoxides, hydrides, alkyls, aryls, and amides are preferred as condensing agents. It is thought that the acidic hydrogen in the ll-position of the compound of Formula V is first neutralized with the formation of the alkali metal salt which then reacts with the aminoalkyl halide. Alkali metal salt-forming reagents which suitably serve as condensing agents include sodium amide, lithium amide, sodium hydride, butyl lithium, potassium t-butoxide, phenyl lithium, etc. If desired, the alkali metal salt of the dioxodibenzothiadiazepine reactant (Formula V) may be prepared as a separate preliminary step before carrying out the reaction with the carboxamidoalkyl halide. A further quantity of condensing agent in addition to that used to form the alkali metal salt is not then required.

The intermediates of Formula II obtained by this process are identical with those prepared by the demethylation procedure described, and may be used interchangeably therewith for hydrolysis to the desired pharmaceutical products of the present invention. The following examples serve to illustrate in detail the teaching of the above disclosure.

EXAMPLE 1 6-methyl-11-[3-(N-carbethoxy-N-methylamino) 1 propyl] -5,5-dix0dibenz0[1,2,5]thiadiazepine (see also Example 41) Seven grams (0.02 mole) of 6methyl-11-(3-dimethylamino-l-propyl) 5,5 dioxodibenzo[1,2,5]thiadiazepine dissolved in 70 ml. of toluene is added in dropwise fashion at 25 C. to a solution of 7 g. of ethyl chloroformate in 70 ml. of toluene during a period of 1 hr. The resulting suspension is refluxed for 23 hrs, allowed to cool to room temperature, and then extracted with three 70 ml. portions of 10% aqueous hydrochloric acid. The organic layer is separated,'dried over magnesium sulfate, and the solvent removed by distillation in vacuo. The product remains as a tan, somewhat sticky mass weighing 5.8 g.

4 EXAMPLE 2 6-metlzyl-11-(3-methylamino-I-pr0pyl) -5,5-di0x0dibenzo[1,2,5] thiadiazepine hydrochloride 6 methyl 11 [3-(N-carbethoxy-N-methylamino)-lpropyl1-5,5-dioxodibenzo[1,2,5]thiadiazepine, 7.3 g., is refluxed with a solution of 3 g. of potassium hydroxide in 200 ml. of n-butanol for 7 hrs. under a nitrogen atmosphere. The solvent is removed by distillation in vacuo at C. and the residue dissolved in a mixture of 100 ml. of water and 100 ml. of benzene. Insoluble material is removed by filtration and the benzene layer of the filtrate is separated. The benzene solution is washed with water and then extracted with three 30 ml. portions of dilute aqueous hydrochloric acid. The acid extracts are adjusted to an alkaline pH by treatment with 40% aqueous sodium hydroxide and extracted with benzene. The benzene extracts are combined, dried over magnesium sulfate, and then treated with 5 N ethanolic HC], resulting in precipitation of the desired product as the hydrochloride salt. The entire mass is then concentrated to dryness and the residue triturated with a solvent mixture of methanol and ether. This material is then recrystallized from a mixture of methanol and diisopropyl ether to yield the purified product, M.P. 201.5202.5 C.

Analysis.-C, 55.35; H, 5.99; N, 11.35.

This produce exhibits infrared absorption maxima (1% trituration in KBr) at the following wave lengths: 2.9, 3.4, 3.7, 6.8, 7.5, 8.7, 13.0, 14.0;/.. It has a water solubility of 100 mg./ml. A 1% solution thereof exhibits pH 5.8 and no precipitation occurs when the solution is adjusted to pH 7 with 0.1 N sodium hydroxide.

EXAMPLES 3-40 Additional demethylalion examples The procedure of Example 1 is applied to the starting materials listed below. Preparation of the starting materials is described in copending application Ser. No. 328,- 460 filed herewith. The resulting N-carbethoxyamino-N- methylamino compounds are then hydrolyzed according to the procedure of Example 2. Immediately following the name of each starting material is given the name of the intermediate N-carbethoxyamino compound, and below that, occupying the third line of each grouping, the name of the end product. Example numbers are assigned to each of the intermediates and end products for identification purposes in referring to this tabulation.

Examples 3-40:

Starting material Intermediate End Product 6-methyl-11-(2-dimethylamino-l-ethyl)-5,5-dioxodi benzo[1,2,5]thiadiazepine 6-methyl-11-[2-(N-carbethoxy-N-methylamino)-1- ethyl]-5,5-dioxodibenzo[1,2,5]thiadiazepine 6-methyl-1 1- (Z-dirnethylamino-2-propyl -5 ,5 -dioxodibenzo[1,2,5]thiadiazepine 6-methyl-11-[N-carbethoxy-N-methylamino)-2-propyl]- 5 ,5 -dioxodibenzo 1 ,2,5 thiadiazepine 6-methyl-1 1-(Z-methylamino-Z-propyl)-5 ,5 -dioxodibenzo[ 1,2,51thiadiazepine 6-methyl-11-(3-dimethy1amino-1-butyl)-5,5-dioxodibenzo 1,2,5 thiadiazepine 2-bromo-6-methyl-1 1- 3-methylaminol-propyl) -5 ,5

dioxodibenzo[1,2,5]thiadiazepine 6-methyl-8-ethoxy-11-(Z-dimethylamino-l-ethyl)-5,5-

dioxodibenzo[1,2,5]thiadiazepine 6-methyl-8-ethoxy-11-[2-(N-carbethoxy-N-methylamino) -1-ethyl] -5,5-dioxodibenzo l ,2,5 ]thiadiazepine 6-methyl-8-ethoxy-11-(2-methylamino-1-ethyl)-5,5-

dioxodibenzo 1,2,5 thiadiazepine 6-methyl 7-trifluoromethyll 1-(3-dimethylarnino-1- propyl) -5 ,5 -dioxodibenzol 1,2,5 thiadiazepine 6-methyl-7-trifiuoromethyl-1 1- 3- (N-carbethoxy-N- methyla mino 1 -propyl] -5 ,5 -dioxodibenzo[ 1,2,5] thiadiazepine 6-methyl-7-trifluoromethyl-1 1- 3-methylamino- 1- propyl)-5,5-dioxodibenzo[1,2,5]thiadiazepine EXAMPLE 41 Alternate preparation for the product of Example 1 A. Preparation of N-(3-chl0r0pr0pyl)-N-methylcarbamic Acid Ethyl Ester.3-dimethylamino-l-propyl chloride hydrochloride, 158 g. (1 mole), is dissolved in 250 ml. of water and converted to the free base by treatment with aqueous sodium hydroxide. The 3-dimethylamino-1- propyl chloride is recovered by extraction into ether and the ether extracts dried. The dry ether solution of 3- dimethylamino-l-propyl chloride is then slowly added to a solution of 326 g. (3.0 mole) of ethyl chloroformate in 600 ml. of benzene with stirring and while maintaining the reaction temperature at 20-25 C. The ether is removed by distillation and the remaining benzene solution is refluxed for 2 hrs. The solution is then allowed to cool to room temperature and unreacted amine removed by washing the solution with 200 ml. of 1 N hydrochloric acid. The benzene solution is then dried over magnesium sulfate and concentrated to dryness yielding the desired intermediate.

B. 6 methyl 11 [3 (N carbethoxy N methylam ino) 1 propyl] 5,5 di0x0dibenz0[1,2,5]thiadiazepine.A mixture of 19.5 g. (0.075 mole) of 6- methyl-5,5-dioxodi benzo[1,2,5]thiadiazepine (copending application Ser. No. 328,476 of Abraham Weber filed herewith) and 170 ml. of dry dimethylformamide is warmed to 100 C. in a reaction vessel fitted for exclusion of atmospheric moisture. A suspension of 10.5 g. (0.225 mole) of sodium hydride in mineral oil is added portionwise to the warm dimethylformarnide solution. The yelw suspension of the sodium salt of the thiadiazepine starting material which forms is treated with 27.0 g. (0.150 mole) of N-(3-chloropropyl)-N-methylcarbamic =acid ethyl ester, and heated at about 120 C. for 3 hrs. It is allowed to cool to room temperature, poured into ice water, thereby to precipitate the desired product which is suitable, after drying, for further transformation according to Example 2.

EXAMPLES 42-57 Additional alkylation processes The procedure of Example 41B is applied to the following nuolearly substituted 5,5-dioxodi benzo[1,2,5] thiadiazepine raw materials, preparation of :which is described in copending application Ser. No. 328,476 of Abraham Weber, filed herewith. The resulting N-carbethoxy N methylamino-1-propyl intermediates, the names of which follow the names of the various raw materials, are then hydrolyzed by the procedure of Example 8 2 to 3-methylamino-l-propyl end products. The names of the latter are listed third in each of the sequences listed below. Example numbers have been assigned to the names of the intermediates and end products of the present invention which are contained in the following listing.

Examples 4257 Starting Material Intermediate End Product 6-rnethyl-7-ethylthio-5 ,5 -dioxodibenzo[ 1,2,5 thia diazepine 6-methyl-7-ethylthio-1 1- [3- (N-car-bethoxy-N-methylamino) -1-propyl] -5,5-dioxodibenzo 1 ,2,5 thiadiazepine 6-methyl-7-ethylthio-1 1- 3-methylaminol-propyl) -5 ,5

dioxodibenzo[1,2,5]thiadiazepine 2-ethanesulfonyl-6-methyl-5 ,5 -dioxodibenzo 1,2,51thiadiazepine 2-ethanesulfonyl-6-methyl-11-[3-(N-carbethoxy-N- methylamino)-1-propyl]-5,5-dioxodibenzo[1,2,5] thiadiazepine Z-ethanesulfonyl-6-methyl-1 l-(3-methylamino-1-propyl 5,5-dioxodibenzo[1,2,5]thiadiazepine. 2-methoxy-6-methyl-5,S-dioxodibenzo[1,2,51thiadiazepine 2-methoxy-6-methyl-1 l- [3 (N-carbethoxy-N-methylamino) l-propyl] -5 ,5 -dioxodibenzo 1,2,5 thiadiazepine 2-methoxy-6-methyl-1l-(3-methylamino-1-propyl)-5,5-

dioxodibenzo[1,2,5]thiadiazepine 6-methyl-9-acetyl-5 ,5 'dioxodibenzo 1 ,2,5 thiadiazepine 6-rnethyl-9-acetyl-1l-[3-(N-carbethoxy-N-methylamino)- l-propyl] -5,5-dioxodibenzo[1,2,5]thiadiazepine 6-methyl-9-acetyl-1 l- B-methylamino-l-propyl) -5 ,5

dioxodibenzo[1,2,5]thiadiazepine 2-ethylthio-6-methyl-5 ,5 -dioxodibenzo 1,2,5 thiadiazepine 2-ethylthio-6-methy1-1 1-[3-(N-carbethoxy-N-methylamino) -l-propyl] -5,5-dioxodibenzo 1,2,5] thiadiazepine 2-ethylthio-6-methyl-1 1- 3 -methy1aminol-propyl -5 ,5

dioxodibenzo 1,2,51thiadiazepine 6-methyl-7-ethanesulfonyl-S,S-dioxodibenzo[1,2,51thiadiazepine 6-n1ethyl-7-ethanesulfonyl-1 l- [3- (N-carbethoxy-N- methylamino)-1-propyl]-5,5-dioxodibenzo[1,2,5]- thiadiazepine methylamino)-1-propyl] -5 ,5 -diox0dibenzo 1,2,5 thiadiazepine o-rnethyl-8-dimethy lamino-1 1- 3-methylamino- 1 -propyl) 5 ,5 -dioxodibenzo 1,2,5 thiadiazepine 2-trifluoromethyl-6 methyl-5 ,5 -dioxodibenzo 1 ,2,5

thiadiazepine 2-trifiuoromethyl-fi-methyl-l 1-(3-methylamino-1-propy1) 5 ,5 -'dioxodibenzo[ 1,2,5 Jthiadiazepine EXAMPLE 58 Parenteral solution A solution for injection is prepared as follows. 6-methyl- 11 (3 methylamino 1 propyl 5,5 dioxodibenzo- [1,2,5]thiadiazepine hydrochloride, 500 g., is dissolved in 9 l. of water for injection, U.S.P. The solution is adjusted to pH 7.0 with dilute aqueous sodium hydroxide and diluted to 10 l. and filtered to remove fibers and other insoluble material. It is then filled into 1 ml. glass ampoules, the ampoules sealed, and sterilized by heating in an autoclave at 121 C. for min.

EXAMPLE 59 Tablets A dry blend of 165 g. of lactose, U.S.P. and 1 g. of acacia powder, U.S.P. is prepared and granulated with a 10% w./w. starch paste containing 3 g. of corn starch, U.S.P. The moist granulation is strained through a No. 1.2 screen and dried at 130 F. until the moisture is less than 2% by weight. The granules are then reduced in size by passage through a No. screen and the following materials are thoroughly blended with the screened granulation: 6 methyl 11 (3 methylarnino 1 propyl) 5,5 dioxodi benzo[1,2,5]thiadiazepine hydrochloride, 25.0 g.; talc, 4.0 g.; and stearic acid, powdered, 2.0 g. The resulting blend is then compressed into tablets, each conatining 25.0 mg. of active ingredient.

EXAMPLE 60 6 methyl 8 carboxy 11 (3 methylamino 1- propyl)-5,5-dioxodibenzo [1,2,5] thiadiazepine (Example 34), 3 g., is dissolved in 30 ml. of 5 N ethanolic hydrogen chloride and the solution is refluxed for approximately 2 hrs. It is then evaporated to dryness by distillation of the solvent and excess hydrogen chloride. The residue is crystallized to yield the purified product.

6 methyl 11 (3 methylamino 1 propyl) 5,5- dioxodibenzo [1,2,5]thiadiazepine hydrochloride, the prodof Example 2, is a amphetamine.

While several particular embodiments of this invention are shown above, it will be understood that the invention is not to be limited thereto, since many modifications may be made, and it is contemplated by the appended claims to cover any such modifications as fall within the true spirit and scope of the invention.

10 What is claimed is: 1. A compound selected from the group having the formula and the acid addition salts thereof, wherein R is from one to two substituents selected from the group consisting of hydrogen, halogen, methyl, trifluoromethyl, 'alkoxy, alkylthio, and alkylsulfonyl, and contains up to four carbon atoms;

R is selected from the group consisting of lower alkyl having 1 to 4 carbon atoms and benzyl;

R is selected from the group consisting of hydrogen,

halogen, methyl, trifluoromethyl, dimethylamino, dimethylsulfa-myl, carboxy, carbalkoxy, alkylthio, alkylsulfonyl, a-lkoxy, and alkanoyl, and contains up to four carbon atoms;

Alk is selected from the group consisting of ethylene and trimethylene having up to one alkyl substituent containing up to two carbon atoms;

R contains up to four carbon atoms and is selected from the group consisting of alkyl.

2. The compound of claim 1 wherein R and R are hydrogen, R is methyl, Alk is ethylene, and R is alkyl having up to four carbon atoms.

3. The compound of claim 1 wherein R and R are hydrogen, R is methyl, Alk is trimethylene, and R is alkyl having up to four carbon atoms.

4. 6 methyl 11 (3 methylamino 1 propyl)- 5,5-dioxodibenzo[1,2,5]thiadiazepine.

5. 6 methyl 11 (3 methylamino 1 propyl)- 5,5-dioxodibenzo[1,2,5]thiadiazepine hydrochloride.

6. A compound selected from the group having the formula s o2-N R Ru \N/ lk-Y wherein R is from one to two substituents selected from the group consisting of hydrogen, halogen, methyl, trifluoromethyl, alkoxy, alkylthio, and alkylsulfonyl and contains up to four carbon atoms;

R is selected from the group consisting of lower alkyl having one to four carbon atoms and benzyl;

R is selected from the group consisting of hydrogen, halogen, methyl, trifiuo-romethyl, dimethyla-mino, dimethylsulfa-myl, carbalkoxy, alkylthio, alkylsulfonyl, alkoxy, and alkanoyl and contains up to four carbon atoms;

Alk is selected from the group consisting of ethylene and trimethylene having up to one alkyl substituent containing up to tWo carbon atoms;

Y is selected from the group consisting of -NR'CO R and wherein R is a lower alkyl group atoms, and

R contains up to four carbon atoms and is selected from the group consisting of alkyl, or acyloxyalkyll.

containing up to four carbon I 7. The compound of claim 6 wherein R and R are hydrogen, R is lower alkyl having up to four carbon atoms, Alk is ethylene, and Y is NR'CO R wherein R and R are alkyl containing up to four carbon atoms.

8. The compound of claim 6 wherein R and R are hydrogen, R is lower alkyl having up to four carbon atoms, Alk is trimethylene, and Y is NRCO R wherein R and R are alkyl having up to four carbon atoms.

9. 6 methyl 11 [2 (N carbethoxy N methylamino) 1 ethyl] 5,5 dioxodibenzo[1,2,5]thiadiazegame.

10. 6 methyl l1 [3 (N carbethoxy N methylamino) -1-propyl] -5,5-dioxodibenzo[ 1,2,5] thiadiazepine.

References Cited UNITED STATES PATENTS Jacob et a1 260268 Yale et a1. 260--293.4 Schindler et a1 260239 Yale et a1 260293.4 Dietrich et al 260-239 ALEX MAZEL, Primary Examiner.

HENRY R. J ILES, Examiner.

JAMES W. ADAMS, 111., Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP HAVING THE FORMULA 